The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells.

摘要: Basophil numbers are typically elevated in chronic myeloid leukemia (CML) and increase during disease progression. Histamine is an essential mediator marker of basophils highly up-regulated CML. We examined the biochemical basis histamine synthesis CML cells. The CML-specific oncoprotein BCR/ABL was found to promote expression histidine decarboxylase (HDC) Ba/F3 Moreover, tyrosine kinase inhibitors imatinib (STI571) nilotinib (AMN107) decreased levels HDC mRNA BCR/ABL-transformed cells, CML-derived basophil cell line KU812, primary Synthesis be restricted compartment clone depend on signaling through PI3-kinase pathway. cells also expressed receptors (HRs), including HR-1, HR-2, HR-4, histamine-binding CYP450 isoenzymes which serve as targets HR antagonists. HR-1 antagonists loratadine terfenadine, bind CYP450, were counteract proliferation whereas no growth inhibition observed with antagonist fexofenadine not targeted or metabolized by CYP450. DPPE, inhibitor isoenzymes, produced Together, these data show that promotes production certain HR-targeting drugs exert antileukemic effects